ABSTRACT This program project grant features a highly integrated team of scientists with diverse relevant expertise to determine the mechanistic basis for the observed ethnic differences in susceptibility to lung cancer in cigarette smokers. Their studies are based on a major lead form the Multiethnic Cohort study which demonstrated that, for the same number of cigarettes smoked, and particularly at lower levels of smoking, self-identified African Americans and Native Hawaiians have a higher incidence of lung cancer than Whites while Latinos and Japanese Americans have a lower incidence. They will build on their important results from the first five years of this project demonstrating significant differences in nicotine metabolism and carcinogen uptake which partially explain the relatively high risk of African Americans and the low risk of Japanese Americans. Four projects will draw on their expertise in epidemiology, genetics, epigenetics, biostatistics, analytical chemistry, biochemistry, and tobacco carcinogenesis. Project 1, Ethnic Differences in Smoking-Related Biomarkers and Risk of Lung Cancer, will evaluate whether DNA methylation profiles differ across racial/ethnic groups, investigate the relationship between genome-wide DNA methylation and biomarkers of smoking dose, and the relationship of nicotine metabolism, tobacco carcinogen and toxicant biomarkers, and DNA methylation to lung cancer in current smokers. Project 2, 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) ?-Hydroxy Glucuronides, Metabolic Profiling and Activation, will determine the effect of CYP2A6 genotype on NNK metabolic activation in Japanese American smokers with differing CYP2A6 activity, and use unique deuterated NNK metabolic profiling methods to characterize NNK metabolism in these groups with diverse lung cancer risk. Project 3, Ethnic/racial Differences in Metabolism and DNA Adduct Formation by 1,3-Butadiene, will investigate ethnic differences in butadiene-DNA adducts in the urine of smokers from different ethnic groups and determine the relationship of DNA adducts to lung cancer and the influence of carcinogen metabolizing genes on DNA adduct formation, repair, and toxicity/mutagenicity. Project 4, Oral Cell DNA Adducts and Urinary Biomarkers to Investigate Ethnic/Racial Differences in Lung Cancer Susceptibility, will quantify known and previously unknown DNA adducts in oral mucosa cells of Native Hawaiian, White, and Japanese American smokers and will investigate urinary biomarkers of acrolein, crotonaldehyde, inflammation, and oxidative damage among smokers and non-smokers from these ethnic groups. These projects are supported by three superb cores with unique world class expertise: Core A, Administrative; Core B, Clinical and Biomarkers; and Core C, Biostatistics. In summary, we present a unique multidisciplinary approach to study mechanisms of ethnic/racial differences in lung cancer susceptibility. We expect to continue to generate sound, exciting, and relevant multidisciplinary mechanistic data leading to new insights for lung cancer prevention. RELEVANCE. Lung cancer is the leading cause of cancer death in the world, causing 1,589,800 deaths in 2012. Approximately 90% of lung cancer incidence and mortality in the U.S. is due to cigarette smoking. Our approach to lung cancer prevention is based on an understanding of mechanisms of tobacco-induced cancer, which will lead to new insights for prevention. This program project grant investigates these mechanisms using established differences in ethnic/racial susceptibility as a base.